Medulloblastomas (MBs) are prototypical primitive neuroectodermal tumors (PNETs) of the cerebellum, and they are among the most common pediatric brain tumors. Until recently, understanding of the basic cell biology and pathogenesis of these tumors remained largely enigmatic. However, it is now established that many MB cells and nearly all MB cell lines resemble immature central nervous system (CNS) neurons or their progenitors. Since MBs occur almost exclusively in young children when heterotopic immature neurons and neuroectodermal progenitors are most common in cerebellum, MBs may arise from the failure of neuroectodermal progenitor cells to undergo programmed cell death or to complete a normal program of neuronal differentiation. This may be followed by the acquisition of genetic lesions in residual neuroectodermal progenitors that induce neoplastic transformation. Further, the inappropriate expression of neurotrophins and their cognate receptors in neuroectodermal progenitors and MBs may play a key role in the induction and progression of MBs. To gain insights into the initiation and progression of these common pediatric brain neoplasms, and to identify molecular defects that interrupt normal developmental events that might prevent neuroectodermal progenitor cells from exiting the cell cycle and terminally differentiating into neurons or undergoing cell death, we plan to examine the relationship between cell death, proliferation and neuronal differentiation in authentic human MBs and PNETs as well as in cell lines and transgenic mouse models of these tumors. We also will characterize the neurotrophin receptors expressed in the normal developing cerebellum, as well as in human MBs and human MR-derived cell lines. This information will then be used to design strategies to induce neuronal differentiation or cell death in MB cell lines by engineering these cell lines to express neurotrophin receptors and to respond to their cognate neurotrophins. These studies are unique in that they extend from the assessment of human biopsy samples to the analysis of cell culture and animal models of MBs and PNBTs. Taken together, the studies will provide novel and important insights into key processes (i.e. cell death, proliferation, differentiation) that are central to tumor initiation and progression. These studies also will clarify the role that neurotrophins play in the emergence and progression of MBs and PNBTs. Insights into these basic biological processes could set the stage for the development of novel gene therapies for MBs.